The present invention relates to a process for the preparation of 1,2,4-triazolin-5-one derivatives which are useful as intermediates in the synthesis of therapeutic agents. In particular, the present invention relates to the preparation of the compound 3-chloromethyl-1,2,4triazolin-5-one.
Compounds of formula (A), below, which are described in International patent specification No. WO 95/16679 (published Jun. 22, 1995), are potent and selective substance P (or neurokinin-1) receptor antagonists. 
wherein
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl, and
(4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) xe2x80x94CF3; and
Z is C1-4alkyl.
In particular, the compound 2-(R)(1(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(s)-(4-fluorophenyl)4(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine is a potent, long-lasting, nonpeptide substance P antagonist based upon its ability to displace [125I]substance P from human NK1 receptors (see Hale et al., J. Med. Chem. (1998) 41, 4607). This compound is, therefore, a potential therapeutic candidate for a range of afflictions including chemotherapy-induced emesis, depression and anxiety.
International patent specification No. WO 95/16679 describes the preparation of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine (hereinafter referred to as Compound A), which has the structure: 
by a two-step process starting from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)3-(S)-(4-fluorophenyl)morpholine. With reference to Examples 70 and 75 in WO 95/16679, Compound A is prepared as follows: 
More recently, International Patent Publication No. WO 99/65900 (published Dec. 23, 1999) described a convenient, efficient process which utilizes a one-step alkylation with 3-chloromethyl-1,2,4-triazolin-5-one. The synthesis of the chloromethyltriazolinone 1 is described in Examples 2 and 3 of WO 99/65900 which used the base-catalysed cyclisation of an acyl semicarbazide (Scheme 1). Hence, benzyloxyacetyl chloride was condensed with semicarbazide hydrochloride under modified Schotten-Baumann conditions to give crude adduct 2. This was not purified but, instead, was heated in dilute NaOH to induce cyclisation thus giving triazolinone 3 in 60% yield from benzyloxyacetyl chloride. Hydrogenolytic removal of the benzyl protecting group, using ammonium formate as the hydrogen source, gave the water soluble alcohol 4 in excellent yield (98%). Treatment of this compound with thionyl chloride then afforded chloromethyltriazolinone 1 as a stable crystalline solid in 87% yield. 
While this synthesis of the chloromethyltriazole 1 allowed the study of the subsequent alkylation reaction to afford Compound A, the cost of the starting acid chloride and the number of steps involved detracted from its viability for large scale synthesis.
There is therefore a need for a simple and efficient synthesis of 3-chloromethyl-1,2,4triazolin-5-one and analogous compounds, that utilizes readily available starting materials.
Thus, in a first aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) 
wherein
R represents hydrogen, C1-10alkyl, haloC1-10alkyl or aryl; which comprises:
(i) reacting a triaryl- or trialkylorthoester of formula (II) 
xe2x80x83wherein each R1 independently represents C1-10alkyl, or aryl, with a semicarbazide of formula (III) 
xe2x80x83or a salt thereof, in an organic solvent; and
(ii) collecting the resultant compound of formula (I).
In the compounds of formulae (I) and (II), preferably R is hydrogen or, more particularly, a halomethyl group, especially chloromethyl.
In the compounds of formula (II), preferably each R1 is the same. In particular, R1 is preferably a methyl group.
A salt of the compound of formula (III) is preferably used such as a halide, especially the chloride. In other words, the compound of formula (III) is semicarbazide.HClxe2x80x94i.e. 
Suitable organic solvents of use in the above reaction include alcohols. Most preferably, the above reaction is effected in methanol.
Conveniently, the above reaction is effected at room temperature.
According to an alternative aspect of the present invention, the compound of formula (I) may be prepared by the reaction of a compound of formula (IV) 
or a salt thereof, wherein R and R1 are as previously defined, with. a compound of formula (III) in the presence of an alcoholic solvent.
This reaction proceeds via the in situ formation of an orthoester of formula (II). Thus, in the compound of formula (IV), R1 is preferably a methyl group, and the solvent is preferably methanol. 
A salt of the compounds of formula (IV) is preferably used such as a halide, especially the chloride. In other words, the compound of formula (III) is semicarbazide.HClxe2x80x94i.e.
As used herein, the term xe2x80x9cC1-10alkylxe2x80x9d as a group or part of a group, means a straight or branched alkyl group containing from 1 to 10 atoms. Particularly preferred are C1-6alkyl groups including methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Especially preferred is methyl.
As used herein, the term xe2x80x9chaloC1-10alkylxe2x80x9d means a straight or branched alkyl group containing from 1 to 10 carbon atoms wherein said alkyl group is substituted by one or more halogen atoms. Suitable halogen atoms include chlorine, bromine or iodine, most especially chlorine. Preferably said alkyl group is substituted by one halogen atom.
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, NO2, cyano, SRa, SORa,SO2Ra, CORa, CO2Ra, CONRa Rb , C2-6alkenyl, C2-6alkynyl, C1-4alkoxyC1-4alkyl or xe2x80x94O(CH2)m Oxe2x80x94, where Ra is hydrogen, C1-4alkyl or fluoroC1-4alkyl. Preferably said phenyl, biphenyl or naphthyl group is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy. Most preferably, aryl is a phenyl group.
According to a further aspect of the present invention, there is provided a method for the synthesis of the compounds described in International Patent Publication No. WO 95/16679. In particular, there is provided a method for the synthesis of compounds of formula (A) as described herein. Said method comprises the preparation of a compound of formula (I) according to the method described and claimed herein, followed by one or more synthetic steps to complete the synthesis of the desired compound. Suitable methods for completing the synthesis are described, in particular, in International Patent Publication No. WO 99/65900.
In particular, there is provided the use of a compound of formula (I) when prepared according to the method described and claimed herein in the preparation of the compound 2-(R)(1-(R)-(3,5-bis(trifluoromethyl)-phenyl) ethoxy)-3-(S)-(4-fluorophenyl)4-(3-(5-oxo-1H,4H-1,2,4-triazolo) methyl)morpholine; and pharmaceutically acceptable salts thereof.
According to a yet further aspect of the present invention, there is provided the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-morpholine, or a pharmaceutically acceptable salt thereof, prepared by the reaction of a compound of formula (I) with 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-S)-(4-fluorophenyl)morpholine, characterised in that said compound of formula (I) is prepared according to the method described and claimed herein. Suitable methods for completing the synthesis are described, in particular, in International Patent Publication No. WO 99/65900.
The following non-limiting examples illustrate processes according to the present invention: